Molecular Tracing of Prostate Cancer Lethality - Beyond the Abstract
Prostate cancer invasion and progression to metastasis is driven by epithelial to mesenchymal transition (EMT) and phenotypic interconversion to mesenchymal to epithelial transition (MET). E-cadherin and the tetraspanin protein family, cell-surface proteins which maintain cellular organization and structure, cell-cell adhesions, strengthen integrin-mediated cellular adhesion, cell, motility, and polarity are valuable biomarkers in prostate cancer. Specifically utilizing bioinformatic integration, CD151 was found to serve a role as a tumor suppressor in prostate cancer progression, largely localized at cell-cell junctions and with an inverse association with Gleason grade and tumor staging. To understand the journey to metastasis, one must first identify genetic drivers of tumor aggression. A mouse model containing knockout PTEN and SMAD4 harbored more aggressive disease. In addition, expression of CCND1, SPP1, and Gleason score can improve the prognostic accuracy for biochemical recurrence (BCR). Further, resistance to anoikis, defined as apoptosis induced by cellular detachment from the surrounding extracellular matrix, is critical to survival in circulation after extravasation from the primary site. Indeed, numerous targets have been identified in anoikis-resistance, such as activation of tyrosine kinase signaling, MAPK signaling, and Ras family of small GTPases. Additionally, in prostate cancer, Nuclear factor-kappa B (NF-κB) can mediate anoikis resistance as a downstream mediator of Notch activity, which could drive the development of mCRPC, via a pro-inflammatory mechanism.
Prostate-specific antigen (PSA) remains the standard biomarker for prostate cancer; however, it is not without its shortcomings. PSA lacks specificity for prostate cancer, and further, cannot risk-stratify patients which may be high risk for metastasis or hormone therapy-resistant. As such, multiple molecular markers have emerged over the last two decades with potential prognostic significance. An early example identified 31 genes involved in cell cycle progression, which significantly can predict BCR and mortality. However, this is still an unmet need, despite the intense profiling of the phenotypic and molecular landscape, genes regulating EMT and tumor invasion, in addition to those mediating angiogenesis, are invaluable to patient prognosis. As such, one must consider overexpression of SOX4 and SPOCK1 (EMT) and VEGFA and HIF-1a (angiogenesis) in genomic profiling.
Though most patients will initially respond to ADT, the majority will ultimately experience treatment resistance. A major driver of ADT resistance is high intratumoral levels of androgens that activate androgen receptor (AR) signaling. Castration (chemical or surgical) does not lower these levels, possibly related to steroidogenic enzymes produced by the adrenal glands. 17B-hydroxysteroid dehydrogenase type 5 and 3B-hydroxysteroid dehydrogenase type 1 (3BHSD1) are critical to adrenal steroidogenesis, with the former potentially useful to abiraterone and enzalutamide resistance, and the latter a potential biomarker for predicting ADT resistance and emergence of CRPC. There are multiple other mechanisms associated with ADT resistance, such as reactivation of AR secondary to gain of function mutations, development of neuroendocrine prostate cancer (NEPC), and dedifferentiation into a stem cell-like state. Further, a multitude of genes has been identified as markers of resistance to taxanes, docetaxel (1st line) and cabazitaxel (2nd line chemotherapy), and consequential prostate cancer mortality.
With the identification of gene signatures that predict BCR, lymph node invasion, and metastasis, noninvasive biomarker panels can allow for a better understanding of the patient’s risk before prostatectomy. CTCs with divergent expression of genes have already been identified with potential prognostic value. Prognostic markers in mCRPC patient serum have also outperformed current nomograms in predicting 12- and 24-month survival. Finally, we must also appreciate the challenges associated with clinical biomarker validation, including confounding effects of tumor heterogeneity in bulk sequencing technologies and effective means of acquiring clinical specimens. The rapid increase in the availability of germline testing also calls for much-needed standardization of testing indications and gene panels. Continuing this work with rigor in gaining precise molecular insights will allow for improved risk stratification to precisely guide treatment tailored to individual patients.
Written by: Andrew Katims, MD, MPH, Alice Wang, & Natasha Kyprianou, MBBS, Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY
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